The project is designed to generate a robust pipeline of anti-trypanosomatid drugs with product profiles suitable for clinical trials and deployment. It will be conducted by a highly organized Trypanosomatid Drug Development Consortium (TDDC) with extensive and diverse expertise, technical capabilities, facilities, and ongoing studies with these pathogens. The TDDC consortium includes SBRI/University of Washington, UCSF, University of North Carolina at Chapel Hill, and the Eskitis Institute of Griffiths University, each of which has collaborative or consulting ties with various other public and private institutions. The consortium has the essential technologies and equipment, compound and natural product libraries, in vitro and in vivo models, expertise, and project management skills to conduct the project. It will use a milestone based, decision matrix supported, product development approach to: 1) Identify trypanosomatid candidate drug targets by comprehensive literature and informatic analyses and prioritize them for experimental validation and initial assay development. 2) Develop high throughput screens (HTSs) for prioritized targets. The HTSs will use sensitive and specific reporter systems, typically with recombinant proteins, and will be robust, reproducible, and sensitive. 3) Screen selected libraries of synthetic and natural product compounds with these HTSs as well as trypanosomatid cell viability assays. Active compounds in natural product hits will be isolated and their structures determined, and IC50s will be determined for all promising hits. 4) Perform hit-to lead chemistry to provide high-quality lead candidates and iterative lead optimization and SAR analysis using compound analogs. 5) Lead-like compounds will be tested for efficacy and toxicology, ADME, and PK to generate a select set of compounds for clinical analyses. 6) Generate a centralized project and information management system that will be instituted as an information-based interface among the sites and as a community resource. It will facilitate workflow and aid coordination and decision making. The outcome will be a set of targets and chemical entities distributed along the pipeline from target discovery to preclinical validation thus providing a rich ongoing resource of drug candidates for clinical studies.